Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1

Abstract

Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1β induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1β triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation.

De Novo Polycomb Recruitment: Lessons from Latent Herpesviruses

“…This combined histone H3K27/S28 methyl/phospho switch has been observed on cellular promoters following cell stress [166,167] and in neurons following stimulation [168]. A similar mechanism for potentially overcoming H3K9me3 has been observed on the HSV genome in reactivation [97,165]. However, as yet whether H3S28p is linked to reactivation of any of the human herpesviruses is unknown.…”

“…One potential mechanism is via recruitment of histone demethylases (to remove K27 methylation) and/or deubiquitinase. A role for K27 demethylases has been found for full HSV [97,105,165], HCMV [111] and KSHV [89,90]. However, the mechanism of recruitment remains unknown.…”

“…There also remains the possibility of Polycomb eviction for reactivation, which may occur independently of histone demethylase activity. The initial induction of gene expression during HSV reactivation has been shown to be independent of the activities of the K27 histone demethylases [97,165]. However, the mechanism by which gene expression is able to initiate under these conditions is not known.…”

De Novo Polycomb Recruitment: Lessons from Latent Herpesviruses

“…One potential mechanism is via recruitment of histone demethylases (to remove K27 methylation) and/or deubiquitinase. A role for K27 demethylases has been found for full HSV [ 97 , 105 , 164 ], HCMV [ 111 ] and KSHV [ 89 , 90 ]. However, the mechanism of recruitment remains unknown.…”

“…There also remains the possibility of Polycomb eviction for reactivation, which may occur independently of histone demethylase activity. The initial induction of gene expression during HSV reactivation has been shown to be independent of the activities of the K27 histone demethylases [ 97 , 164 ]. However, the mechanism by which gene expression is able to initiate under these conditions is not known.…”